Contrasting Features of Insulin Dependent Diabetes Mellitus Associated with Neuroectodermal Defects and Classical Insulin Dependent Diabetes Mellitus

ABSTRACT. The Wolfram, or DIDMOAD, syndrome is a rare congenital disease that is associated with diabetes insipidus, insulin dependent diabetes mellitus of an early onset, bilateral optic atrophy and deafness. Urological disorders are usually present as well. We have studied nine patients belonging to five different families. All of the family members were HLA typed (including DR), and islet cell as well as antinuclear antibody determinations were carried out. Although individuals with insulin dependent diabetes mellitus are very prone to have either HLA-DR3 or -DR4 antigens, none of our patients had DR3 antigens and only one was DR4 positive. On the other hand, three of our patients were typed as HLA-DR2 positive. This antigen is uncommon in classical insulin dependent diabetes. In one of the families, the affected siblings did not share the same HLA haplotype. Islet cell and antinuclear antibodies were not found in any of the cases and six of the patients had a small, but significant, insulin secretory reserve. On the basis of some of the clinical features it was also possible to further distinguish between the DIDMOAD syndrome and the classical insulin dependent diabetes mellitus. The differences encountered between classical and DIDMOAD insulin dependent diabetes mellitus—the presence/absence of HLA linkage, HLA-DR2, -DR3 and -DR4 associations, islet cell or antinuclear antibodies, the tendency to ketosis and diabetic retinopathy—indicate that their etiopathogenies are triggered by distinct mechanisms.     

Thyroid hormones and thyroglobulin autoantibodies in insulin dependent diabetes mellitus

Serum T4, FT4, T3, and TSH were measured in a group of children with insulin dependent diabetes mellitus and a control group. In the insulin dependent diabetes mellitus group, serum T3 concentration was significantly lower than the control values. Serum T4, FT4 and TSH level did not differ. The difference in serum T3 concentration was significant between diabetic children with good or poor control. Thyroglobulin antibodies were investigated in diabetic children by Serono's "hTg antibodies" kit. Thyroglobulin antibodies were present in 14.5%. TSH concentration did not differ in antibody positive and negative cases, but one child with diabetes had evidence of moderately impaired thyroid reserve.     

The Study of HLA, ICA and Autoantibodies in Japanese Type 1 Diabetes Mellitus

HLA, ICA (islet cell antibody) and autoantibodies were studied in 65 Japanese patients with type 1 diabetes mellitus to elucidate the existence of immuno-genetic heterogeneity. Patients with autoantibodies had increased frequencies of HLA DRw9 antigen and of HLA haplotype of Bw61-DRw9, and a slow decay of ICA, while patients without autoantibodies had increased frequencies of HLA DR4 antigen and of HLA haplotype of Bw54-DR4, and a rapid decay of ICA. These findings support the concept of immunogenetic heterogeneity in Japanese type 1 diabetes mellitus.     

Permanent neonatal diabetes mellitus: clinical presentation and epidemiology in Oman

AIM: To estimate the accurate incidence and prevalence of permanent neonatal diabetes mellitus, and to determine the clinical profile of this condition in the Sultanate of Oman. METHODS: All children diagnosed as having permanent neonatal diabetes mellitus between 1991 and 1995 in Oman were included in the study. RESULTS: The mean incidence was 2.2 per 100 000 live births/year and the prevalence among under 5s during 1995 was 2.0/100 000. Intrauterine growth retardation was noted in all (mean birthweight 1.86 kg), and diabetic ketoacidosis (mean plasma glucose 34.4 (SD 8.7) mmol/l, mean pH 7.17 (SD 0.09) in 80%. Hypertriglyceridaemia (mean serum triglyceride 19.06 (6.13) mmol/) was constant. No infant had clinical or immunological evidence of congenital viral infections. None had C-peptide excretion or circulating islet cell antibody during diagnosis or follow up. The other important features were parental consanguinity in all, HLA DR3/DR4 association in 80%, development of autoimmune hypothyroidism in one and observation of autoimmune disorders (insulin dependent diabetes mellitus and Hashimoto's thyroiditis) in family members. CONCLUSIONS: These findings strongly suggest an immune mediated aetiology for diabetes mellitus. The reported incidence of permanent insulin dependent neonatal diabetes mellitus in Oman is the highest in the world.     

Residual insulin secretion in insulin dependent diabetes mellitus.

The residual insulin secretory capacity of 244 children with insulin dependent diabetes mellitus was determined by measurement of their 24 hour urinary C peptide excretion. An inverse linear relation was found between the residual B cell secretion and the duration of diabetes. The age at onset of diabetes did not affect the residual B cell function significantly.     

Insulin dependent diabetes in Asians.

Type 1 diabetes is said to be extremely rare in children in India, where diabetes treated with insulin may be due to chronic pancreatic disease or malnutrition. To see whether typical type 1 diabetes occurred in Asian children in the United Kingdom, all known Asian children with diabetes in industrial West Yorkshire were ascertained. A total of 17 such children were studied; of these, seven were from three multiplex families and two fathers from these families had diabetes. All children were ketosis prone and developed diabetes while resident in the UK. There were significant increases in HLA-B8 and HLA-DR3 and increases in HLA-DR4 and HLA-DR3/DR4, while HLA-B15 was absent. Islet cell antibodies, either IgG or complement fixing, were present in four of 18 subjects tested, all of whom had disease of short duration. The prevalence of type 1 diabetes in Asian children aged 15 years or less in West Yorkshire was 36/100,000, assuming complete ascertainment. It is concluded that typical type 1 diabetes may occur in Asian children and this condition may be more common in families who have migrated to the UK.     

Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus

A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus.     

Prediction of type 1 diabetes mellitus—a report on three cases

In three children (patients 1, 2 and 3) insulindependency was predicted 28, 32 and 4 months, respectively before the disease became clinically manifest, by the finding of islet cell antibodies at that time.These retrospective findings support the evidence for a long pre-diabetic phase in childhood diabetes, marked by the presence of islet cell antibodies, as well as the linkage of HLA-antigens to the susceptibility to this disease. The possibility of detecting pre-diabetic states in children before the endogenous insulin secretion decreases to the point of producing clinical symptoms support efforts by basic scientists to develop techniques for immunological intervention early in the course of the disease.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - ICCA islet cell cytoplasmatic antibodies - CF-ICCA complement-fixing-islet cell cytoplasmatic antibodies - ICSA islet cell surface antibodies     

Postprandial hyperinsulinaemic hypoglycaemia and type 1 diabetes mellitus.

A patient with severe postprandial hyperinsulinaemic hypoglycaemia (PPHH) for 4 years developed type 1 diabetes mellitus. She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. PPHH prior to the onset of type 1 diabetes mellitus has not been previously described and may be a prodrome of type 1 diabetes mellitus.     

Association of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness. The Wolfram or DIDMOAD syndrome.

Seven patients with a rare syndrome of diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), neurosensory deafness (D), atony of the urinary tract, and other abnormalities (Wolfram or DIDMOAD syndrome) are reported. Of the seven patients, three siblings were followed up for 10-17 years. All seven patients had diabetes mellitus and optic atrophy; six had diabetes insipidus; and in the four patients investigated there was dilatation of the urinary tract. The severity of diabetes varied, and all required insulin for control of the hyperglycaemia. In one patient the course of the disease simulated maturity onset diabetes of the young; another presented with ketoacidosis; but none had haplotypes usually associated with insulin dependent diabetes mellitus. The diabetes insipidus responded to chlorpropamide, suggesting partial antidiuretic hormone deficiency. Onset of optic atrophy and loss of vision occurred relatively late and progressed slowly, although in one patient there was a rapid deterioration in visual acuity. Deafness was mild, of late onset, and of sensorineural origin. A degenerative process affecting the central and peripheral nervous system can explain all the manifestations of the syndrome except diabetes mellitus. The pathogenesis of the diabetes mellitus remains obscure.     

Diabetes mellitus in cystic fibrosis: genetic and immunological markers

Family history, as well as genetic and immunological markers of diabetes mellitus, were studied in cystic fibrosis (CF) patients with and without diabetes mellitus. Positive family history of diabetes mellitus in first-degree relatives was found in only 6 of 210 (3%) CF patients, with no difference between non-diabetic and diabetic patients. The frequency distributions of the HLA types DR3, DR4 and DR3/4, which normally confer susceptibility to insulin-dependent diabetes mellitus and of HLA-DR2, which normally confers resistance to insulin-dependent diabetcs mellitus, were not different in non-diabetic CF patients, diabetic CF patients and normal subjects. The genotypic frequencies of tumor necrosis factor-β and of heat shock protein 70, located within the HLA region on chromosome 6, in CF patients with diabetes were not different from those in patients with insulin-dependent diabetes mellitus, while non-diabetic CF patients and normal subjects shared other patterns. The frequencies of the interleukin-1β alleles, located on chromosome 2, were not different in non-diabetic and diabetic CF patients, insulin-dependent diabetic patients and normal subjects. Islet cell cytoplasmic antibodies. measured before, at and after the diagnosis of diabetes in 33 diabetic CF patients and in 32 matched non-diabetic CF patients, were detected in only 2 of 236 (0.8%) serum samples; m a pre-diabetic patient and in a non-diabetic control patient. Birth weights were not different in diabetic and non-diabetic CF patients, arguing against the importance of the intrauterine environment as a determinant in the transmission of diabetes mellitus in CF patients. We conclude that diabetes mellitus in CF is without family history of diabetes mellitus, HLA-DR association, and serological evidence for autoimmune destruction of the β-cells. The significance of similar frequcncies of tumor necrosis factor-β and heal shock protein 70 alleles in insulin-dependent diabetic patients and diabetic CF patients remains to bc determined.     

Simultaneous onset of type 1 diabetes in monozygotic twins younger than 1 year

This report describes type 1 insulin deficient diabetes mellitus (IDDM) arising in identical twins aged under one year. One twin presented with symptoms and was diagnosed with type 1 IDDM; the diagnosis of type 1 IDDM was simultaneously made in the second twin without clinical symptoms. Both twins were positive for anti-GAD (glutamic acid decarboxylase) antibody at first, and then positive for islet cell antibodies. Interestingly, the twins have four susceptible HLA DR and DQ genes together that are usually recognized separately in IDDM patients in Japan.     

Changes in lymphocyte subsets in children with newly diagnosed type 1 diabetes mellitus

The aim of this study was to assess changes in selected peripheral blood lymphocyte subsets in children and adolescents with newly diagnosed type 1 diabetes mellitus (DM) and determine the correlation between these changes and other immunological markers. The study involved a group of 39 patients aged 2-14 years and a control group. The number of T- and B-lymphocytes and the number of CD4, CD8, CD4/HLA-DR, CD8/HLA-DR, CD5/CD20 subsets were measured by flow-cytometry using monoclonal antibodies. Islet cell antibodies (ICA) and antibodies to glutamic acid decarboxylase (GADA) were assessed. In both the diabetic and control groups the number of T-and B-lymphocytes were within normal limits. In patients with DM, the percentage of CD5+/CD20+ cells was significantly increased compared with the control group (p < 0.0001). ICA were positive in 80% of patients and GADA in nearly 65%. A positive correlation between the CD5/CD20 subset and ICA and GADA was found. In patients with a high percentage of CD5+/CD20+ lymphocytes, a higher percentage of activated subsets (CD4/HLA DR and CD8/ HLA DR) was detected. In conclusion: CD5/ CD20 lymphocyte subsets are a good additional marker of autoimmunological processes in DM.     

Classification of Type 1 and Type 2 Diabetes Mellitus from Studies of ICA, HLA and Insulin Secretory Capacity

We studied ICA, HLA and insulin secretory capacity in 87 children with positive urinary screening and more than 2 points in the oral glucose tolerance test in order to establish criteria by which they could be classified into type 1 or type 2 diabetes mellitus. Fifty-five non-obese, ketosis-prone insulin dependent diabetic children were used as controls for type 1 diabetes mellitus. Our conclusions were as follows: 1. Type 1 diabetics were non-obese (on insulin therapy), ICA positive, ketosis-prone, had an insulin secretory capacity (Z IRI) of less than 100/nU/ml, and most of them possessed HLA-Bw54-DR4 or DRw9, DRw53 but did not possess Bw52-DR2 haplotype. 2. In the patients who were treated by dietary regimens alone for certain periods, however, insulin secretory capacities gradually deteriorated and they finally became insulin dependent. The children of this group who were not obese during insulin therapy and possessed an HLA haplotype identical to that in type 1 diabetes, regardless of ICA, might be classified as having slowly progressive type 1 diabetes. 3. The major difference between type 1 and slowly progressive type 1 diabetes was a family history of diabetes. Genetic factors might modify the clinical course of type 1 diabetes mellitus. 4. If the sensitivity of ICA or related autoantibodies to islet cells can be detected more readily, it should become easier to distinguish between type 1 and 2 diabetes.     

Islet autoantibodies and insulin dependent diabetes mellitus in cystic fibrosis

Cystic fibrosis-related diabetes mellitus (CF-DM) is thought to be secondary to beta-cell destruction by fibrous tissue replacing the exocrine pancreas. The aim of this study was to investigate the hypothesis that other factors may also be responsible. Glutamic acid decarboxylase (GAD) and islet cell (IA-2) antibodies were measured by quantitative ELISA in a group of patients with CF (n=30) in comparison to a group of newly diagnosed DM type 1 (IDDM) patients (n=30) and normal subjects (n=30). GAD antibodies were positive (>32 ng/ml) in 50% of the CF, 93% of the IDDM and 0% of the control group. IA-2 antibodies were detected (>0.9 U/ml) in 40% of the CF, 93% of the IDDM and 0% of the control group. Among the fifteen CF patients with positive GAD and IA-2 antibodies, four already had IDDM and another five abnormally low (<45 mU/l) first phase insulin response (FPIR) indicating a prediabetic state. We conclude that factors other than mechanical may be involved in the development of CFDM. The presence of autoantibodies predicting IDDM supports the hypothesis that CF-DM may have a multifactorial pathogenesis.     

Type 1 diabetes mellitus associated with nephrotic syndrome

Nephrotic syndrome (NS) in a patient with diabetes mellitus (DM) first suggests the diagnosis of diabetic nephropathy. However, glomerular diseases other than diabetic nephropathy have been reported in patients with DM. We present a child with type 1 DM (DM1) associated with NS. A 3 year-old boy who was diagnosed with DM1 developed proteinuria in nephrotic range at the 10th month of follow-up. He had remission on steroid treatment without any problem in glycemic control as he was given tapered daily doses instead of an alternate day regimen. He relapsed at the 7th month of follow-up, and cyclophosphamide treatment brought about remission. He had HLA A24, DR4 and DR53 antigens in common with previously reported cases of DM-NS association. The immunological basis of these diseases may have a causal effect on the association, but the etiopathogenesis is still unclear.     

Islet cell and other organ-specific autoantibodies in healthy first-degree relatives to insulin-dependent

The presence of organ-specific autoantibodies including islet cell surface, cytoplasmic and cytotoxic as well as thyroid-gastric antibodies were determined in healthy, non-diabetic, first-degree relatives to 30 insulin-dependent diabetic (IDDM) children. Thirty healthy families without family-history of diabetes mellitus served as controls. The prevalence of organ-specific autoantibodies among the healthy members in the diabetic families was increased compared to the control families (p less than 0.005). Islet cell cytoplasmic antibodies were only detected in diabetes families, since 23% (7/30) of the probands and 7% (2/31) of the siblings were positive and all others negative. Organ-specific autoantibodies were associated with HLA DR3 only in the diabetes families (p less than 0.025) while autoantibody positive members in the control families were associated with HLA B7 (p less than 0.01). This study suggests that childhood IDDM occurs in families with an increased prevalence of organ-specific autoantibodies.     

Hyporesponsiveness to intradermal administration of hepatitis B vaccine in insulin dependent diabetes mellitus

The immune response to intradermal or intramuscular hepatitis B vaccine in 18 children with insulin dependent diabetes mellitus (IDDM) compared with 24 healthy children was studied. Patients were divided into responders, hyporesponders, and non-responders according to their antihepatitis B serum concentrations after hepatitis B vaccination. We also studied HLA class II antigen distribution and did delayed type hypersensitivity (DTH) tests on children with IDDM and controls. No difference in the immune response (antihepatitis B surface antigen antibody titres) was found with intramuscular administration, whereas with intradermal administration a statistically lower immune response (p < 0.001) was observed in children with IDDM v controls. This hyporesponsiveness cannot be attributed to HLA class II antigen distribution because their frequency was the same in both groups of children with IDDM. It is suggested that the poor immune response to intradermal hepatitis B vaccine may be due to impaired macrophage activity resulting in failure of antigen presentation, which may be of importance in the immune dysfunction in children with IDDM. This hypothesis is suggested by a significantly lower score on a DTH test to a battery of antigens in the IDDM group when compared with controls. It is therefore suggested that when the hepatitis B vaccination is offered to children with IDDM it may be preferable to give it intramuscularly.     

Islet Cell and Other Organ-specific Autoantibodies in Healthy First-degree Relatives to Insulin-dependent

ABSTRACT. The presence of organ-specific autoantibodies including islet cell surface, cytoplasmic and cytotoxic as well as thyroid-gastric antibodies were determined in healthy, non-diabetic, first-degree relatives to 30 insulin-dependent diabetic (IDDM) children. Thirty healthy families without family-history of diabetes mellitus served as controls. The prevalence of organ-specific autoantibodies among the healthy members in the diabetic families was increased compared to the control families ( p <0.005). Islet cell cytoplasmic antibodies were only detected in diabetes families, since 23% (7/30) of the probands and 7% (2/31) of the siblings were positive and all others negative. Organ-specific autoantibodies were associated with HLA DR3 only in the diabetes families ( p <0.025) while autoantibody positive members in the control families were associated with HLA B7 ( p <0.01). This study suggests that childhood IDDM occurs in families with an increased prevalence of organ-specific autoantibodies.     

The challenge of childhood diabetes mellitus in India

The prevalence of DM is about 0.4/1000 children with a lower incidence in the rural areas. Children comprise 3–5% of the total diabetics. A study of 55 pediatrie cases of DM (1980-84) showed that only 22 (40%) had ketoacidosis on admission. Ten (18.2%) had onset of illness before 4 years of age. HLA antigen studies in childhood IDDM have shown a positive linkage disequilibrium with Bw21 (RR-12.7), and DR3 (RR=16.6). Prevalence of islet cell antibodies (ICA) was 30.9% (n = 110) as compared with 0.8% in controls. Antibodies against Coxasckie B2 virus were increased (75.5% vs 46.4% in controls). The C-peptide content was substantially low. Malnutrition related DM occurs in adolescents in some parts of India. It is characterized by moderate hyperglycemia, low serum glycerol, relative insulin insensitivity, and pancreatic malformation/calcification in about 1/4 of subjects. There is no association with HLA antigens or ICA, and the precise etiology is unclear. Mortality was 3.6% in patients admitted in our hospital but is higher in other regions due to poverty and relative lack of health care facilities.